2.1 Heart physiology
In this chapter we provide a physiological contextualization in order to introduce key knowledge about the heart activity, in particular regarding its autonomic regulation, which is on the basis of HRV.
The heart is one of the most important organs of the entire human system since it is responsible for rhythmically pump blood all over the body enabling the transport of vital nutrients and oxygen to the cells. The four chambers that compose the heart (see Figure 2.1) have different roles in this hard and essential task. The chambers from the right side (right atrium and right ventricle) deliver deoxygenated blood, that arrives from the systemic circulation, to the lungs, through the pulmonary circulation, while the chambers from the left side (left atrium and left ventricle) deliver oxygenated blood, coming from the lungs, to the entire body, through the systemic circulation [2].
This vital function is regulated by the Central Nervous System (CNS) and it is ac-complished thanks to the work of the cardiac muscle that, when electrically stimulated, makes the heart contract and relax in a synchronized way. The electrical stimulation is made through a complex network of cardiac muscle fibers that conduct a wave of electrical current with a specific and well defined pattern over the whole heart before every normal heartbeat, resulting in potential differences at the surface of the body that can be easily measured with specific surface electrodes producing a signal known as Electrocardiogram (ECG) [9, 10]. The ECG signal has an extreme importance due to is potential as a diagnose and research tool.
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Figure 2.1: Heart diagram. Taken from [1].
2.1.1 Electrophysiology of the heart
To better realize the electrical behavior of the heart, it is necessary to analyze the behavior of a single heart muscle cell (myocyte) (see Figure 2.2), then understand the organization of the electrical structure of the heart and finally, understand how the electrical waves travel through that structure.
The cardiac muscle that forms the middle layer of the heart walls, more precisely the myocardium1, is a specific kind of muscle that is composed of heart muscle cells called myocites. The process of electric depolarization of the myocytes occurs by the inflow of sodium ions across the cell membrane while the repolarization is achieved by the outflow of potassium ions across the cell membrane, producing an action potential similar to that of nerve cells (around 100 mV). However, the duration of the cardiac impulse is higher than the one verified in the nerve cell or even in the skeletal muscle.
One of the most important differences between the tissue from skeletal and cardiac muscle tissues is that, despite the presence of striations in both, the second type of muscle can transmit the electric activation from one cell to any of the adjacent ones
1The thick, contractile middle layer of uniquely constructed and arranged muscle cells (cardiac muscle) that form the bulk of the heart wall [11].
2.1. HEART PHYSIOLOGY 7
Figure 2.2: Electrophysiology of the heart.The different waveforms for each of the specialized cells found in the heart are shown. The latency shown approximates that normally found in the healthy heart. Taken from [2].
thanks to the presence of gap-junctions2, which means that the electrical waves can be spread in any direction [2,10].
To ensure the heart electrical activity the myocardium has a series of localized nodes with specific electrical roles, responsible for the electrical discharges that happen periodically within the heart, which induces the muscular activity of the heart and consequently the blood pumping throughout the body.
In normal conditions, the heart, is first stimulated by the SA node [12], that is localized in the right atrium at the superior vena cava (see Figure 2.2) and is the primary pacemaker3 of the heart. Given the self-excitatory properties of the nodal-cells, this node has the responsibility to activate the muscular cells in the right atrium and to propagate the activation to the rest of the atria, initiating the heartbeat. It has an intrinsic frequency of 100 to 120 beats per minute (bpm). However, the resulting frequency is normally lower, on the order of 70 bpm, due to the complex nature of the processes occurring since the initial stimulation until the complete depolarization of the
2Low-resistance pathways that interconnect cardiac muscles.
3A myocardial cell displaying automaticity.
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atria. The activation is then transmitted to the ventricles through the Atrioventricular (AV) node, since the electrical impulse cannot cross through the non-conducting fibrous barrier that separates the atria from the ventricles.
The AV node is located at the boundary between the atria and the ventricles (see Figure 2.2), and provides the only path for the electrical waves to reach the ventricles, as noted above. It works like a secondary pacemaker that, in case of fail in the electrical reception, will set the beat at a lower frequency (50 bpm). When the electrical impulses reach the AV node, coming from the SA node, the beat will be set normally, since the SA node has an higher frequency which inhibits the one set by the AV node. Moreover the AV node works as a safety system that momentarily delays the propagation of the electrical potential, avoiding the consequences of rapid atrial potentials arriving to the ventricles.
After the electrical potential has crossed the mentioned barrier, it enters the bundle of His, which is a specialized conducting system that has a bifurcation into two bundles branches (right and left) at the septum. Latter, each bundle ramifies into Purkinje fibers. This structure provides the propagation of the electrical impulses from the AV node to the ventricles. As this propagation happens, the ventricular depolarization takes place at a very high speed. Purkinje fibers work as a third pacemaker (15-30 bpm) avoiding any AV node fail.
A refractory period, during approximately 200 ms, where no electric potential can flow through the myocardium, follows the depolarization of the ventricles. Then, a repolarization occurs restoring the myocardium’s resting potential and leaving the heart ready to undergo a new cycle.
As it was described above, the intrinsic frequency of the SA node is the highest among the heart pacemakers. This fact makes the SA node the main pacemaker of the heart which means that it sets the working frequency of the whole heart [2,9,13].
2.1.2 The ECG
An ECG is the result of a graphical recording of the potential differences that are generated at the surface of the thorax during the electrical activity of the heart, using specific surface electrodes and acquisition hardware. Willem Einthoven received the Nobel Prize in Physiology or Medicine in 1924 for his work on “the discovery of the
2.1. HEART PHYSIOLOGY 9
P
Q R
S
ST T
Segment SegmentPR
PR Interval
QT Interval QRS
Complex
Figure 2.3: Normal features of the ECG. Adapted from [3].
mechanism of the ECG”. Einthoven assigned the different patterns of the ECG and described the manifestations of a significant number of disorders on the ECG wave-form [14].
As seen in 2.1.1 the electrical propagation in the heart follows a specific pattern throughout the electrical pathway. This pattern determines the shape of the ECG waveform in normal and abnormal situations. In normal situations, the ECG has the shape present in Figure 2.3. This schematic representation shows the initial P-wave, the main QRS complex and the T-wave. Each of these waves are caused by specific and sequential events that happen along the electrical pathway. The P-wave corresponds to the depolarization of the atria that happens before atrial contraction.
This wave has a low amplitude due to the few quantity of muscle present in the atria.
The QRS complex, which is the highest portion of the ECG waveform and happens simultaneously to the atrial repolarization (not observable in the ECG), reflects the different moments of ventricular depolarization. Finally, the T-wave represents the ventricular repolarization. The period during which ventricular contraction occurs is known as systole, while the period between ventricular contractions is known as diastole.
The description given above refers to the most common shape of the ECG. However, that shape can vary among healthy patients and between healthy and non-healthy
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patients [2,9].
The simplest mathematical model that describe the electrical activity of the heart is known as the “single dipole” model. This model considers the propagation of an action potential between adjacent cardiac cells, as the elementary source of the surface ECG. The intracellular current propagation at the interface of depolarizing and resting tissue forms the the current dipole. The propagation, in the opposite direction, of extracellular current promotes the charge conservation and forms the dipole field. The electrical activity of the heart boils down to a single equivalent dipole whose magnitude and direction correspond to the summation of all the individual dipoles (the time-dependent heart vector M(t)). Since the surface distribution of potentials varies with the body properties, the dipole model assumes that the body is a linear, isotropic, homogeneous and spherical conductor [2].
Understanding of the dipole model is important in order to know the heart vector pattern and to know how to deal with it to accurately acquire the ECG signal.
2.1.3 Abnormalities in the ECG pattern
One of the greatest achievements that ECG has made possible, was the possibility to diagnose cardiac problems through the analysis of an ECG record. The identification of abnormal situations in ECG waveform pattern is of extreme importance to clinicians.
If the SA node fails to initiate the activation of the heart, due to interruptions in the signal transmission along the electrical pathway, each of the other pacemakers could take care of this task. This property of the heart is almost like a plan-b, a normal compensatory response that prevents the heart activity from stoping. This phenomenon is known as escape beats and will lead to abnormal patterns in the ECG, depending on which alternative pacemaker is used.
Another phenomenon that will lead to non-sinus (not normal) pattern is known as ectopic beats, beats that occur earlier than expected and have a significantly different morphology. Ectopic beats, are beats that were not originated in the SA node due to, for example, drugs (e.g., caffeine) or viral infection of the myocardium. They can arise from almost every location in the heart, although the most common are known as atrial, AV junctional or Ventricular Ectopic Beats (VEBs), also called Premature Ventricular Contraction (PVC)(see Figure 2.4). They and are normally characterized
2.2. AUTONOMOUS NERVOUS SYSTEM AND HEART RATE CONTROL 11
Figure 2.4: Ventricular ectopic beat. Taken from [4].
by a broad QRS complex, which happens due to a change in the system used to conduct the action potentials (myocardium instead of the high-speed Purkinji system). Many studies point that these events may be a consequence of poor recovery after traumatic events or may indicate the onset of fatal arrhythmias4 [10].
The identification of ectopic beats, specially VEBs, and another abnormal ECG waveform patterns, are extremely important to detect repeating patterns with patho-logic origin, such as the Ventricular Tachycardia (VT) and fibrillation (atrial and ven-tricular), that may cause serious damages in the heart and be fatal, by setting depo-larization rates incompatible with the pumping rate of the heart or causing circulatory arrest5 [9,10].
Other types of abnormalities that can be detected with the analysis of the ECG waveform pattern are arrhythmias associated with slow rhythms (bradycardia), block-ages in the normal propagation of the electrical activation and ischemia6.
2.2 Autonomous nervous system and heart rate con-trol
As previously discussed, the SA node acts as the primary pacemaker of the heart, setting, in normal conditions, the working frequency of the heart (HR). The SA node activity is regulated by the CNS, more precisely by the ANS, known as the invol-untary motor system. The ANS is responsible for the regulation of internal organs (heart, digestive tract, lungs, bladder and blood vessels). Although the majority of these functions happen unconsciously, there are some involuntary functions that occur consciously, like breathing.
4Any variation from the normal (sinus) rhythm of the heart.
5Termination of blood flow through the cardiovascular circuit.
6When part of the myocardium is not receiving enough blood flow, often caused by disease of the coronary arteries. It will ultimately progress to myocardial cell death.
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The ANS is divided into two sub-systems, the sympathetic and parasympathetic nervous systems. These two systems exert opposite and competing regulating tasks on most organs. The heart is not an exception, since it is innervated by both.
The sympathetic nervous system is often referred to as the “fight or flight” response, since it is activated during physically or mentally stressful situations. It is responsi-ble for HR raising due to the increase in the SA stimulation and for increasing the strength of contractions due to an increase in the propagation velocity of the depolar-ization wave that travels through the heart (slower response - about 5 seconds). The parasympathetic nervous system is like the “rest and digest” mechanism, since it slows down the HR, decreases the Blood Pressure (BP), and increases the digestive system activity (faster response - less than 1 second).
Sympathetic and parasympathetic branches of the ANS interact in an opposite and highly complex way. However, this should be seen more like a complementary interaction rather than a competing interaction. This complementary modulation is known as the sympathovagal balance, which is achieved through the regulation of the levels of activation of the body (vagal and sympathetic tone).
In the specific case of the heart, the vagal regulation is mediated through release of acetylcholine, while the sympathetic regulation is mediated via release of epinephrine and norepinephrine. The acetylcholine promote the response of muscarinic recep-tors. These receptors, when activated, promote the decrease in the speed of the my-ocardium depolarization and consequently a decay in the HR. The epinephrine and norepinephrine, as expected, have an opposite behavior. They activate the β-adrenergic receptors, resulting in the acceleration of the myocardium depolarization and finally in an higher cardiac frequency. This dual regulation does not have a direct effect on the SA node, but change its sensitivity.
In addition to the central control, there are several different receptors in the cardio-vascular and central nervous systems which are responsible for feedback mechanisms that can provide quick reflexes, such as tachycardic or bradycardic reflexes on the heart rate. One example of such mechanisms is the arterial baroreflex. It lies upon barore-ceptors which are located on the walls of some large vessels and causes increases in vagal activity and decreases in sympathetic activity due a rise in the blood pressure.
When the pressure increases, the vessels are stretched causing a rapid augmentation in
2.2. AUTONOMOUS NERVOUS SYSTEM AND HEART RATE CONTROL 13
ECG
(a)
(b)
(c)
Figure 2.5: ECG segment with 60 seconds (a), the respective RR intervals (b) and the respective IHRs (c).
baroreceptor discharge rate leading to a bradycardic effect on the heart rate in order to lower the pressure.
It is important to note that in resting conditions, both autonomic branches are thought to have a small baseline activity with a slightly vagal predominance. Therefore oscillations in the HR are mainly dependent on vagal modulation [6,9,10].
2.2.1 Heart rate autonomous control and sympathovagal bal-ance
The increase and decrease of the HR, more precisely, the Instantaneous Heart Rate (IHR), is a consequence of the continuous modulation of the heart (SA node) by the vagal and sympathetic branches of the ANS, as previously noted (see Section 2.2). This modulation is responsible for oscillations in the interval between consecutive heartbeats as well as the oscillations between consecutiveIHRs. In Figure 2.5, it is possible to see the oscillations between consecutive RR intervals and oscillations between consecutive
IHRs of a typical ECG segment.
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Many terms were used in the past, but “HRV” has become the term currently widely accepted to describe such phenomenon.
Since Heart Rate Variability (HRV) describes the variations in the interval between consecutive heart beats, it has been pointed out, along the last three decades, as a powerful marker of the activity of the ANS, namely the sympathovagal balance [6,9].